US5929065A - Method for treating sleep disorders - Google Patents

Method for treating sleep disorders Download PDF

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Publication number
US5929065A
US5929065A US08/609,461 US60946196A US5929065A US 5929065 A US5929065 A US 5929065A US 60946196 A US60946196 A US 60946196A US 5929065 A US5929065 A US 5929065A
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gaba
sleep
nonrems
patient
sleep disorder
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US08/609,461
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Marike Lancel
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Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42Oxazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a method of treating sleep disorders comprising the administration of non-allosteric GABA A agonists.
  • the hypnotics most frequently prescribed for the treatment of sleep disorders are classic benzodiazepines as well as compounds like zolpidem and zopiclone. These compounds shorten sleep latency and increase total sleep time.
  • the pharmacological effect of these compounds is assumed to be due to a modulation of the GABA A receptor ( ⁇ -aminobutyric-acid A receptor); however they neither increase neuronal release of GABA nor block the reuptake of released GABA. They have no direct GABA A agonistic effect either.
  • GABA A receptor modulators exhibit considerable side effects. Especially with the use of benzodiazepines, tolerance and dependency develop rapidly, and rebound insomnia, which will manifest itself by restlessness and somnipathy, emerges upon withdrawal.
  • benzodiazepines and all other common hypnotics cause the following sleep profile.
  • the object underlying the present invention is to provide an effective hypnotic which has no significant side effects and causes a sleep profile essentially corresponding to physiological sleep.
  • the present invention provides a method of treating sleep disorders in a patient in need thereof comprising the administration of a hypnotically effective amount of a non-allosteric GABA A agonist.
  • the present invention is based on the unexpected finding that the GABA A agonists muscimol and THIP (4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridin-3-ol) have very advantageous effects on sleep.
  • the activity profiles of muscimol- and THIP-induced sleep can be summarized as follows:
  • the invention relates to a method of treating sleep disorders in a patient in need thereof comprising the administration of a substance which either directly or indirectly stimulates GABA binding sites of the GABA A receptor in an hypnotically effective amount.
  • a substance which either directly or indirectly stimulates GABA binding sites of the GABA A receptor in an hypnotically effective amount.
  • Substances which stimulate the GABA binding site of GABA A receptors are referred to herein as non-allosteric GABA A agonists.
  • GABA A agonists which exert a direct effect on GABA A receptors, such as muscimol, thiomuscimol, THIP, thioTHIP, isoguvacine,
  • GABA prodrugs such as progabide
  • GABA uptake inhibitors such as tiagabine and
  • GABA transaminase inhibitors such as vigabatrin.
  • the above-mentioned substances having a direct or indirect non-allosteric agonistic effect on the GABA A receptor are therapeutically beneficial in a broad range of sleep disorders, including difficulties in falling asleep, frequent nocturnal arousals, early morning awakening and/or a dissatisfaction with the intensity of sleep.
  • the compounds are particularly suitable for the treatment of elderly patients.
  • the non-allosteric GABA A agonist can be formulated in a manner well-known in the art using common pharmaceutical adjuvants and optionally in combination with other active substances to form common galenic preparations, such as tablets, coated tablets, capsules, powders, suspensions, injectable solutions or suppositories.
  • the compounds can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
  • the compounds can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like.
  • Oral administration is generally preferred.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the disease state to be treated, the stage of the disease, and other relevant circumstances.
  • the compounds can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
  • the compounds of the invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crystallization, increased solubility and the like.
  • the dose to be administered depends on the patient's age and weight as well as the degree and nature of sleep disorder.
  • the non-allosteric GABA A agonists used according to this invention are administered in a dose of 5 mg to 50 mg per day.
  • the administration may be intravenous or intramuscular. However, oral administration is preferred.
  • hypothalamic amount means an amount sufficient to reduce sleep latency, prolong REMS, prolong nonREMS, prolong total sleep or enhance EEG-delta activity during sleep.
  • Muscimol resulted in a dose-dependent increase of nonREMS and REMS and a prolongation of REMS and nonREMS episodes. From the spectral analysis of the EEG within nonREMS, it became evident that muscimol, in particular in higher doses, increases the EEG activity in all frequency bands, most potently, however, at lower frequencies (0.5 to 4 Hz), thought to reflect sleep intensity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US08/609,461 1995-07-13 1996-03-01 Method for treating sleep disorders Expired - Lifetime US5929065A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19525598 1995-07-13
DE19525598A DE19525598C2 (de) 1995-07-13 1995-07-13 Schlafmittel

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US5929065A true US5929065A (en) 1999-07-27

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US (1) US5929065A (da)
EP (3) EP0867184B1 (da)
JP (3) JP3754705B2 (da)
AT (3) ATE207356T1 (da)
AU (1) AU723954B2 (da)
CA (1) CA2226582C (da)
CL (1) CL2003002785A1 (da)
DE (4) DE19525598C2 (da)
DK (3) DK0867178T3 (da)
ES (3) ES2165990T3 (da)
PT (3) PT867178E (da)
WO (1) WO1997002813A1 (da)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030212133A1 (en) * 2000-06-26 2003-11-13 Bryans Justin Stephen Gabapentin analogues for sleep disorders
US20040157876A1 (en) * 2001-05-21 2004-08-12 Elema Michiel O Granular preparations of gaboxadol
US20050137222A1 (en) * 2003-12-18 2005-06-23 H. Lundbeck A/S Treatment of insomnia in human patients
US20050164987A1 (en) * 2003-12-24 2005-07-28 Barberich Timothy J. Melatonin combination therapy for improving sleep quality
US20050171142A1 (en) * 2004-01-30 2005-08-04 Cooper Vincent B. Polymorphic forms of a GABAA agonist
US20050176680A1 (en) * 2003-12-11 2005-08-11 Sepracor, Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US20050215521A1 (en) * 2003-12-22 2005-09-29 Karim Lalji Modafinil combination therapy for improving sleep quality
US20050267176A1 (en) * 2004-02-18 2005-12-01 Sepracor Inc. Dopamine-agonist combination therapy for improving sleep quality
US20060093668A1 (en) * 1999-09-28 2006-05-04 H. Lundbeck A/S Melt granulated composition and modified release dosage form prepared from said composition
US20070032553A1 (en) * 2003-09-10 2007-02-08 Mckernan Ruth Use of gabaa receptor agonists for the treatment of hearing, vestibular and attention disorders, intention tremor and restless leg syndrome
US20080269278A1 (en) * 2004-04-02 2008-10-30 H. Lundbeck A/S Treatment of Impaired Respiratory Function with Gaboxadol
EP3151832A4 (en) * 2014-06-06 2018-01-17 Ovid Therapeutics, Inc. Methods of increasing tonic inhibition and treating secondary insomnia
US10765666B2 (en) 2018-09-20 2020-09-08 Ovid Therapeutics Inc Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
US11364228B2 (en) 2019-12-18 2022-06-21 Ovid Therapeutics Inc. Gaboxadol for therapeutic treatment of 1p36 deletion syndrome
US11690829B2 (en) 2018-12-17 2023-07-04 Ovid Therapeutics Inc. Use of gaboxadol for the treatment of non-24 hour sleep-wake disorder

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US5914333A (en) * 1996-07-31 1999-06-22 Novo Nordisk A/S Treatment of psychotic disorders
WO1999006045A1 (en) * 1997-08-01 1999-02-11 Elan Corporation, Plc Controlled release pharmaceutical compositions containing tiagabine
IE970588A1 (en) 1997-08-01 2000-08-23 Elan Corp Plc Controlled release pharmaceutical compositions containing tiagabine
DK1641456T3 (da) 2003-06-25 2010-06-21 Lundbeck & Co As H Gaboxadol til behandling af depression og andre affektive lidelser
AR045540A1 (es) 2003-09-05 2005-11-02 Lundbeck & Co As H Metodo de elaboracion de 4,5,6,7 tetrahidroisoxazol [5,4-c] piridin-3-ol (thip)
TW200528098A (en) * 2003-12-18 2005-09-01 Lundbeck & Co As H Treatment of insomnia in human patients
GB0417558D0 (en) * 2004-08-06 2004-09-08 Merck Sharp & Dohme Novel combination therapy
EP1848420A4 (en) 2005-01-28 2008-01-23 Merck & Co Inc POLYMORPHIC FORMS OF A GABAA AGONIST
JP5380930B2 (ja) * 2007-07-24 2014-01-08 大正製薬株式会社 睡眠改善剤
ES2781978T3 (es) 2015-03-24 2020-09-09 H Lundbeck As Fabricación de 4,5,6,7-tetrahidroisozaxolo[5,4-c]piridin-3-ol
CA2992734A1 (en) 2015-07-17 2017-01-26 Ovid Therapeutics, Inc. Methods of treating developmental disorders with gaboxadol
US9682069B2 (en) 2015-07-17 2017-06-20 Ovid Therapeutics Inc Methods of treating Dravet syndrome
EP4233861A3 (en) 2016-08-11 2023-10-11 Ovid Therapeutics, Inc. Compositions for treatment of essential tremor
US10071083B2 (en) 2017-02-03 2018-09-11 Ovid Therapeutics Inc Use of gaboxadol in the treatment of tinnitus
AU2018309049A1 (en) 2017-08-04 2020-02-27 Ovid Therapeutics Inc. Use of gaboxadol in the treatment of diabetes and related conditions
EP3883566A4 (en) 2018-11-21 2022-09-07 Certego Therapeutics Inc. GABOXADOL FOR SUICIDE RISK REDUCTION AND RAPID DEPRESSION RELIEF
WO2020118364A1 (en) 2018-12-14 2020-06-18 Raimondo Fazio Martial arts training device
US11597726B2 (en) 2020-05-20 2023-03-07 Certego Therapeutics Inc. Ring deuterated gaboxadol and its use for the treatment of psychiatric disorders
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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060093668A1 (en) * 1999-09-28 2006-05-04 H. Lundbeck A/S Melt granulated composition and modified release dosage form prepared from said composition
US7141606B2 (en) * 2000-06-26 2006-11-28 Warner-Lambert Company Gabapentin analogues for sleep disorders
US20030212133A1 (en) * 2000-06-26 2003-11-13 Bryans Justin Stephen Gabapentin analogues for sleep disorders
US20040157876A1 (en) * 2001-05-21 2004-08-12 Elema Michiel O Granular preparations of gaboxadol
US20070032553A1 (en) * 2003-09-10 2007-02-08 Mckernan Ruth Use of gabaa receptor agonists for the treatment of hearing, vestibular and attention disorders, intention tremor and restless leg syndrome
US20070299055A1 (en) * 2003-12-11 2007-12-27 Sepracor Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US8097625B2 (en) 2003-12-11 2012-01-17 Sunovion Pharmaceuticals Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US20050176680A1 (en) * 2003-12-11 2005-08-11 Sepracor, Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
EP2343073A2 (en) 2003-12-11 2011-07-13 Sepracor Inc. Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US20050137222A1 (en) * 2003-12-18 2005-06-23 H. Lundbeck A/S Treatment of insomnia in human patients
US20050215521A1 (en) * 2003-12-22 2005-09-29 Karim Lalji Modafinil combination therapy for improving sleep quality
US20050164987A1 (en) * 2003-12-24 2005-07-28 Barberich Timothy J. Melatonin combination therapy for improving sleep quality
US20050171142A1 (en) * 2004-01-30 2005-08-04 Cooper Vincent B. Polymorphic forms of a GABAA agonist
US20070259912A1 (en) * 2004-01-30 2007-11-08 Cooper Vincent B Polymorphic forms of a GABAA agonist
US7262300B2 (en) 2004-01-30 2007-08-28 Merck Sharp & Dohme Ltd. Polymorphic forms of a GABAA agonist
US8236958B2 (en) 2004-01-30 2012-08-07 H. Lundbeck A/S Polymorphic forms of a GABAA agonist
US20100004251A1 (en) * 2004-02-18 2010-01-07 Sepracor Inc. Dopamine-Agonist Combination Therapy For Improving Sleep Quality
US8877755B2 (en) 2004-02-18 2014-11-04 Sunovion Pharmaceuticals Inc. Dopamine-agonist combination therapy for improving sleep quality
US20050267176A1 (en) * 2004-02-18 2005-12-01 Sepracor Inc. Dopamine-agonist combination therapy for improving sleep quality
US20080269278A1 (en) * 2004-04-02 2008-10-30 H. Lundbeck A/S Treatment of Impaired Respiratory Function with Gaboxadol
US20100093787A1 (en) * 2004-04-02 2010-04-15 H. Lundbeck A/S Treatment of impaired respiratory function with gaboxadol
EP3151832A4 (en) * 2014-06-06 2018-01-17 Ovid Therapeutics, Inc. Methods of increasing tonic inhibition and treating secondary insomnia
AU2015269667B2 (en) * 2014-06-06 2020-07-30 Ovid Therapeutics, Inc. Methods of increasing tonic inhibition and treating secondary insomnia
EP3795156A1 (en) * 2014-06-06 2021-03-24 Ovid Therapeutics, Inc. Pharmaceutical composition for treating angelman syndrome
US11278529B2 (en) 2014-06-06 2022-03-22 Ovid Therapeutics Inc. Methods for treating aggression associated with Alzheimer's disease
US10765666B2 (en) 2018-09-20 2020-09-08 Ovid Therapeutics Inc Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
US11090293B2 (en) 2018-09-20 2021-08-17 Ovid Therapeutics Inc. Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
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DE69616376T2 (de) 2002-06-27
DE19525598C2 (de) 1997-09-25
DE69616376D1 (de) 2001-11-29
EP0867178A1 (en) 1998-09-30
DK0840601T3 (da) 2002-02-18
DE69616375T2 (de) 2002-07-11
ATE207349T1 (de) 2001-11-15
WO1997002813A1 (en) 1997-01-30
JP3754705B2 (ja) 2006-03-15
DE69616333D1 (de) 2001-11-29
CA2226582A1 (en) 1997-01-30
AU6613796A (en) 1997-02-10
DE19525598A1 (de) 1997-01-16
DE69616333T2 (de) 2002-07-04
DE69616375D1 (de) 2001-11-29
EP0840601B1 (en) 2001-10-24
DK0867178T3 (da) 2002-02-18
ES2166111T3 (es) 2002-04-01
ATE207352T1 (de) 2001-11-15
JPH11509194A (ja) 1999-08-17
CL2003002785A1 (es) 2005-04-08
PT867178E (pt) 2002-04-29
JP2009057382A (ja) 2009-03-19
EP0867178B1 (en) 2001-10-24
AU723954B2 (en) 2000-09-07
PT867184E (pt) 2002-04-29
DK0867184T3 (da) 2002-02-18
PT840601E (pt) 2002-04-29
ES2166110T3 (es) 2002-04-01
EP0867184B1 (en) 2001-10-24
EP0840601A1 (en) 1998-05-13
ATE207356T1 (de) 2001-11-15
EP0867184A1 (en) 1998-09-30
ES2165990T3 (es) 2002-04-01
JP2005047925A (ja) 2005-02-24
CA2226582C (en) 2008-02-19

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